Download Compare and Contrast: IBS/IBD

Irritable Bowel Syndrome: Treatment Overview Focusing on Newly Approved Medications
Southwest Florida Society of Health System Pharmacists
Disclosure
• I, or an immediate family member, including spouse or partner, have no financial relationship(s) relevant to the contents of this continuing education activity Jose Barboza, Pharm.D., C.D.E.
Faculty
Pharmacotherapeutics & Clinical Research
University of South Florida College of Pharmacy
Objectives
Irritable Bowel Syndrome: Definition
1. Describe the pathophysiology of Irritable Bowel Syndrome
2. Review the treatments for Irritable Bowel Syndrome
3. Discuss the use of rifaximin and eluxadoline in treating diarrhea predominant irritable bowel syndrome
• Gastrointestinal (GI) syndrome – Abdominal pain or discomfort – Altered bowel habits – Absence of organic cause
• Recurring symptoms
– Incomplete evacuation
– Urgency
– Bloating
Compare and Contrast: IBS/IBD
Irritable Bowel
Syndrome (IBS)
Pain/ Discomfort
Change in Bowel habits
Inflammatory Bowel
Disease (IBD)
Chronic inflammation
of the intestines
Absence of organic cause
Diarrhea (IBS‐D)
Crohn’s disease (CD)
Constipation (IBS‐C)
Ulcerative colitis (UC)
– Altered bowel function
• Diarrhea predominant (IBS‐D)
• Constipation predominant (IBS‐C)
• Constipation/ diarrhea (IBS‐M)
• Undefined (IBS‐U)
Irritable Bowel Syndrome: Diagnosis
Rome III Criteria for Irritable Bowel Syndrome
Recurrent abdominal pain or discomfort
Three episodes per month
Last 3 months associated
Two or more of…
1
Improvement with defecation
2
Onset associated with change in frequency of stool
3
Onset associated with a change in form of stool
Alternating/Mixed (IBS‐M)
Am J Gastroenterol, 2009. 104 Suppl 1: p. S1‐35.
1
Irritable Bowel Syndrome: Epidemiology
IBS
Pathophysiology
Disturbed GI motility
Visceral hypersensitivity
Psychological stress
Intestinal microflora and inflammation
• Altered levels of 5HT
•
•
•
•
• Prevalence in US: 10‐15%
– More common • Females (~2:1)
• Young adulthood
– 15% of those affected seek medical attention
• Most commonly diagnosed GI condition
• 5HT3 and 5HT4 are extensively found in the gut, responsible for secretion, sensitization, and motility
– 25‐50% of gastroenterologist referrals Clin Epidemiol. 2014; 6: 71–80.
Physiological distribution of 5‐HT
• Prucalopride
• 5HT4 agonist
• IBS-C
CNS – 5%
• Alosetron
• 5HT3 antagonist
• IBS-D
GI tract – 95%
Drugs. 2014 Oct;74(16):1849-70.
• Causes altered GI
Pathophysiology:
• Motility
• Sensitivity
• Secretions
IBS: Dietary Modifications
IBS –Positive Diagnosis and Outcome
•
•
•
•
•
•
•
•
Identify concerns
Basis for patient’s symptoms
Reassurance
Cost effective evaluation
Involve patient in decision making
Provide continuity
Set realistic limits
No association between negative colonoscopy and improved health related quality of life
Gershon, Aliment Pharmacol Ther.,1999
• Avoid caffeine, alcohol, and artificial sweeteners
– Can irritate the gut > laxative effect
•
•
•
•
Evaluate lactose intolerance
Rule out Celiac sprue (1%) Rule out gluten intolerance (6%)
Low FODMAP diet
– Fermentable Oligosaccharides, Disaccharides, Monosaccharides and Polyols
– Poorly absorbed by some
Gastrointest Endosc 2005; 62:892-9.
2
IBS‐C: Non‐Pharmacologic
• Secondary constipation: Correct the cause
• Dietary modification: Basis of therapy
– Gradually increase fiber
– 20‐25 grams/day
• Other lifestyle
– Exercise – Adjust bowel habits – Increase fluid intake IBS: Fiber
Agents and Availability • Agents (Not FDA approved for IBS)
–
–
–
–
Methylcellulose (Citrucel)
Calcium Polycarbophil (FiberCon)
Psyllium (Metamucil)
Barley malt extract (Maltsupex)
• Powders, flakes, granules, tablets, and liquids
• Doses vary, typically administered in divided doses IBS: Fiber
Precautions
•
•
•
•
Severely fluid restrictions
May cause hypersentitivity
Diabetes
Fecal impaction or intestinal obstruction
– Avoid: intestinal ulcerations, stenosis, and disabling adhesions
IBS: Fiber
MOA/ Role in Therapy
• MOA: Contain hydrophilic polysaccharide derivatives
– Absorb water to: Increase bulk, soften the stool, and facilitate peristalsis and elimination
– Effects seen in 2‐3 days
• Role in therapy: – Safest – Acceptable in pregnancy
IBS: Fiber
Adverse Effects/Drug Interactions
• Adverse effects
– Abdominal distention, cramping, and flatulence
• Minimized by gradual increase, resolved with continued use
• Drug Interactions
– Possible binding to digoxin and warfarin
– May bind with tetracyclines
– Separate other medications by 1‐2 hours
IBS: Fiber
Evidence
• Psyllium/ispaghula husk showed improvement over placebo
– NNT=6 (IBS type not differentiated)
• Other agents are similar to placebo
• Psyllium/ispaghula husk (20‐30 g/day) improves constipation
Drugs. 2014 Oct;74(16):1849-70.
3
IBS: Antispasmodics/Anticholinergics
• MOA: Relax smooth muscles in the colon and small bowel • Symptomatic relief – Pain
• Agents: Peppermint oil, hyoscine, cimetropium, pinaverium, mebeverine, and otilonium
• Side effects: Anticholinergic, generally safe
IBS: Antidepressants
• MOA: Improve dysregulation of neuroenteric pathway • Symptomatic treatment: Abdominal pain
– Reserved for patients with severe or refractory pain
• Visceral analgesia, changes in motility, smooth muscle relaxation
• Agents: – Paroxetine, fluoxetine, citalopram, amitriptyline, and imipramine
• Adverse effects (antibiotic dependent): – insomnia, restlessness, sexual dysfunction, nausea, constipation, diarrhea
Drugs. 2014 Oct;74(16):1849-70.
Drugs. 2014 Oct;74(16):1849-70.
IBS: Probiotics
• MOA: restore normal flora
– Alterations may cause
•
•
•
•
Diarrhea‐Predominant IBS (IBS‐D)
Increased fermentation of food Changes in intestinal motor and sensory function, Mucosal immune activation
Malabsorption • Agents:
– Lactobacillus, bifidobacterium, streptococcus, others
– Limitations in clinical trials
• Generally safe
IBS‐D: Loperamide
• Evaluated in randomized controlled trials for IBS‐D
– Effective for treatment of diarrhea
– Not FDA approved for IBS
• No impact on abdominal bloating or global IBS symptoms
• Acute diarrhea: Oral: Initial: 4 mg, followed by 2 mg after each loose stool, up to 16 mg/day
IBS‐D: Alosetron
MOA/Agent
• MOA: Potent and selective 5‐HT3 antagonist – Results in modulation of the enteric nervous system
• Alosetron (Lotronex)
– Approved in chronic, severe IBS‐D for patients who failed to responded to conventional treatments
– Starting dose: 0.5mg BID
– Reassess at 4 weeks
• No adequate control of symptoms: Increase to 1mg BID
– Re‐assess at 4 weeks
• No adequate control of symptoms: Discontinue medication
ACG Task Force on IBS. Am J Gastro. 2009
4
IBS‐D: Alosetron
Restricted Use/Precautions
• Adverse effects (dose related)
– Constipation – GI discomfort/pain
• Restricted FDA use
– Females only
– Enroll in Prometheus prescribing program
• Ischemic colitis (FDA warning)
– 1.1 cases/1,000 patient‐years
• Precautions: Constipation, ischemic colitis
IBS‐D: Alosetron
Contraindications
• Constipation
• intestinal obstruction, stricture, toxic megacolon, gastrointestinal perforation, and/or adhesions
• Ischemic colitis, impaired intestinal circulation, thrombophlebitis, or hypercoagulable state
• Crohn's disease or ulcerative colitis
• Diverticulitis
• Severe hepatic impairment
• Concomitant fluvoxamine use
Chang L et al. Am J Gastro 2010
IBS‐D: Rifaximin
• Broad spectrum antibiotic with low bioavailability – <0.4% absorbed
• FDA approved
• Dose: 550mg TID for 2 weeks
– May be repeated up to 2 times
– Improvement shown in up to 10 weeks
• Showed to improve global IBS symptoms: TARGET 1 & 2
• Adverse effects: Flatulence, abdominal pain, tenesmus, fecal incontinence, nausea, and headaches
• High Cost, Xifaxan 550mg (#60)~ $2000
IBS‐D: Eluxadoline (Viberzi)
• MOA: kappa and mixed mu and opioid receptor agonist, delta opioid receptor antagonist – Decrease pain and intestine contractility
– Shown to improve stool consistency and pain
• Global symptoms, QOL, and adequate relief
• FDA Approved: IBS3001 and 3002
• Dose: 100mg BID
• Unable to tolerate, no gallbladder, mild hepatic impairment: 75mg BID
IBS‐D: Eluxadoline
• Adverse effects
– Constipation (~8% vs. 2.4%), nausea (~7.5% vs. 4.8), vomiting
• Contraindications:
– Severe hepatic impairment, biliary duct obstruction, diseases of the pancreas, alcoholism
5
IBS‐C: Osmotic Laxatives
MOA/ Role in Therapy
Constipation‐Predominant IBS (IBS‐C)
• MOA: Osmotic agent, causes water retention in the stool and increases stool frequency
– Not absorbed systemically
– Onset 1‐4 days

Role in therapy




IBS‐C: Osmotic Laxatives:
Dose/ Side Effects/ Contraindications


Available with and without electrolytes
PEG: Constipation • MOA: Chloride channel activator
– Open chloride channels locally on the GI luminal epithelium
– Stimulates chloride‐rich fluid secretion into the lumen
– Results in softening of the stool and increased motility – Onset: 24‐48 hours
10–30 g or 17–34 g per 120–240 mL QD or BID  Not FDA Approved for IBS
Side effects


Bloating, abdominal discomfort, cramping, flatulence
Contraindications

GI Obstruction IBS‐C: Lubiprostone
Lubiprostone‐ Role in Therapy/ Adverse Effects
Agent: Polyethylene Glycol 3350 (Miralax): Rx or OTC
IBS‐C: Chloride Channel Activator
Lubiprostone‐ MOA/ Agent


Low doses for constipation
Bowel cleansing before diagnostic or colorectal procedures
Safe use chronically, studied in up to 6 months

Agent: Lubiprostone (Amitiza) 
FDA Approved to treat chronic constipation in adults (Rx)

IBS‐C: 8 mcg BID with food
 Constipation: 24mcg BID with food
IBS‐C: Guanylate Cyclase‐C agonist
Linaclotide‐ MOA/ Agents
• MOA: Guanylate cyclase‐C agonist
• Role in therapy
– Chronic constipation in those who fail first‐line agents
• Adverse effects – Nausea (dose dependent), diarrhea, abdominal pain, flatulence, headaches, dyspnea
– Pregnancy category C
• Contraindication
– GI obstruction
– Stimulates the secretion of chloride and bicarbonate into the intestinal lumen
– Increased intestinal fluid and accelerated GI transit
– Decreased visceral pain • Agent: Linaclotide (Linzess)
– FDA Approved for IBS‐C: • 290mcg PO QD on an empty stomach • ≥30 minutes prior to the first meal of the day
• Chronic Constipation: 145 mcg PO QD on an empty stomach at least 30 minutes prior to the first meal of the day
6
IBS‐C: Serotonin Agonists
Prucalopride
IBS‐C: Linaclotide
Side Effects/ Contraindications

• MOA
• Side effects:
– Diarrhea, abdominal pain, flatulence
• Pregnancy category C
• Contraindicated
– GI obstruction
– Children <6 years old
• Agents
– Prucalopride‐ Not available in USA, available in Europe
Treatment Algorithm
Diarrhea Predominant
Increase: Fiber and Liquid intake
Diet: Lactose‐fee and caffeine‐free diet, avoid other diarrhea causing agents
Add bulk‐forming laxatives, consider antispasmodic agents
Add loperamide or antispasmodic agents
Add 5HT‐3 antagonists (alosetron)
Add psychotherapeutic behavior modifications, consider antidepressants
Drugs. 2014 Oct;74(16):1849-70.
Summary

No adverse CV effects compared to placebo
Altered Bowel Motility: IBS-C
Psyllium, osmotic laxatives
(PEG), sorbitol/lactulose,
lubiprostone, linaclotide, 5HT4
receptor agonists, STW5
Emerging Therapies
•IBAT
Symptomatic treatment
Constipation Predominant

Tegaserod‐ withdrawn from the market due to CV adverse events likely due to its actions on hERG channel Prucalopride: no actions on hERG channel and higher affinity to ‐5HT4
Prucalopride has been safely tolerated in clinical trials
Altered Bowel Motility: IBS-D
Rifaximin, loperamide, 5HT3
receptor antagonists
Emerging Therapies:
•Bile acid sequestrants
•Crofelemer
•ASA derivatives
Altered Bowel Motility
Stress management and patient educations
Add 5HT‐4 agonists (prucalopride) or guanylate cyclase‐c agonist (linaclotide)
Safety

– Selective high affinity 5‐HT4
receptor agonist
– Promotes enteric neurons to stimulate the peristaltic reflex, intestinal secretions, and GI 
motility Pain:
Antispasmodics,
antidepressants,
probiotics, STW5,
melatonin
Emerging Therapies
•Mixed visceral Muopioid
•Receptor
agonists/antagonists,
•Pregabalin
•Selective visceral K
opioid receptor agonist
•H1 receptor
antagonists
•NK receptor
antagonists
Pain
Bloating
Drugs. 2014 Oct;74(16):1849-70.
Bloating:
Antispasmodics,
antiflatulents,
probiotics, linaclotide,
rifaximin,
antidepressants:
citalopram, fluxoetine
Questions?
• IBS and IBD result in similar symptoms and can be difficult to manage
– Diagnosis can be difficult – IBS: Increased morbidity
– IBD: Increased morbidity and mortality
• Cost of therapy can be high
• Monitor for medication adverse effects, precautions, and contraindications
[email protected]
7